Sex- and age-dependent susceptibility to ventricular arrhythmias in the rat heart ex vivo.

The incidence of life-threatening ventricular arrhythmias, the most common cause of sudden cardiac death (SCD), depends largely on the arrhythmic substrate that develops in the myocardium during the aging process. There is a large deficit of comparative studies on the development of this substrate in both sexes, with a particular paucity of studies in females. To identify the substrates of arrhythmia, fibrosis, cardiomyocyte hypertrophy, mitochondrial density, oxidative stress, antioxidant defense and intracellular Ca2+ signaling in isolated cardiomyocytes were measured in the hearts of 3- and 24-month-old female and male rats. Arrhythmia susceptibility was assessed in ex vivo perfused hearts after exposure to isoproterenol (ISO) and hydrogen peroxide (H2O2). The number of ventricular premature beats (PVBs), ventricular tachycardia (VT) and ventricular fibrillation (VF) episodes, as well as intrinsic heart rate, QRS and QT duration, were measured in ECG signals recorded from the surfaces of the beating hearts. After ISO administration, VT/VFs were formed only in the hearts of males, mainly older ones. In contrast, H2O2 led to VT/VF formation in the hearts of rats of both sexes but much more frequently in older males. We identified several components of the arrhythmia substrate that develop in the myocardium during the aging process, including high spontaneous ryanodine receptor activity in cardiomyocytes, fibrosis of varying severity in different layers of the myocardium (nonheterogenic fibrosis), and high levels of oxidative stress as measured by nitrated tyrosine levels. All of these elements appeared at a much greater intensity in male individuals during the aging process. On the other hand, in aging females, antioxidant defense at the level of H2O2 detoxification, measured as glutathione peroxidase expression, was weaker than that in males of the same age. We showed that sex has a significant effect on the development of an arrhythmic substrate during aging. This substrate determines the incidence of life-threatening ventricular arrhythmias in the presence of additional stimuli with proarrhythmic potential, such as catecholamine stimulation or oxidative stress, which are constant elements in the pathomechanism of most cardiovascular diseases.

Role of Oxygen Starvation in Right Ventricular Decompensation and Failure in Pulmonary Arterial Hypertension.

Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.

Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma.

BACKGROUND: Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator. OBJECTIVE: Since MM is associated with increased arginase expression, resulting in the consumption of ʟ-arginine, precursor for NO synthesis, our aim was to test if cardiotoxicity mediated by MM and MM therapeutic, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved endothelial function. METHODS: We used a mouse Vĸ*MYC model of non-light chain MM. Cardiac function was assessed by echocardiography. RESULTS: MM resulted in progressive left ventricular (LV) systolic dysfunction, and bortezomib exacerbated this effect, leading to significant impairment of LV performance. An arginase inhibitor, OAT-1746, protected the heart against bortezomib- or MM-induced toxicity but did not completely prevent the effects of the MM+bortezomib combination. MM was associated with improved endothelial function (assessed as NO production) vs. healthy controls, while bortezomib did not affect it. OAT-1746 improved endothelial function only in healthy mice. NO plasma concentration was increased by OAT-1746 but was not affected by MM or bortezomib. CONCLUSIONS: Bortezomib exacerbates MM-mediated LV systolic dysfunction in a mouse model of MM, while an arginase inhibitor partially prevents it. Endothelium does not mediate either these adverse or beneficial effects. This suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the NO pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in MM.

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

Right Ventricle Remodelling in Left-Sided Heart Failure in Rats: The Role of Calcium Signalling.

Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to RVD due to left-sided HF is not fully elucidated. Rats underwent LAD ligation to induce extensive left ventricle (LV) myocardial infarction (MI) and subsequent left-sided HF. Sham-operated animals served as controls. After 8 weeks of follow-up, the animals underwent LV and RV catheterisation, and systolic function and intracellular Ca2+ signalling were assessed in cardiomyocytes isolated from both ventricles. We demonstrated that rats with LV failure induced by extensive LV myocardial infarction also develop RV failure, leading to symptomatic biventricular HF, despite only mildly increased RV afterload. The contractility of RV cardiomyocytes was significantly increased, which could be related to increased amplitude of Ca2+ transient, preserved SERCA2a activity and reduced Ca2+ efflux via NCX1 and PMCA. Our study indicates that RV failure associated with post-MI LV failure in a rat model cannot be explained by a decline in cardiomyocyte function. This indicates that other factors may play a role here, pointing to the need for further research to better understand the biology of RV failure in order to ultimately develop therapies targeting the RV.

New potential treatment for cardiovascular disease through modulation of hemoglobin oxygen binding curve: Myo-inositol trispyrophosphate (ITPP), from cancer to cardiovascular disease.

The human body is a highly aerobic organism, which needs large amount of oxygen, especially in tissues characterized by high metabolic demand, such as the heart. Inadequate oxygen delivery underlies cardiovascular diseases, such as coronary artery disease, heart failure and pulmonary hypertension. Hemoglobin, the oxygen-transport metalloprotein in the red blood cells, gives the blood enormous oxygen carrying capacity; thus oxygen binding to hemoglobin in the lungs and oxygen dissociation in the target tissues are crucial points for oxygen delivery as well as potential targets for intervention. Myo-inositol trispyrophosphate (ITPP) acts as an effector of hemoglobin, shifting the oxygen dissociation curve to the right and increasing oxygen release in the target tissues, especially under hypoxic conditions. ITPP has been successfully used in cancer studies, demonstrating anti-cancer properties due to prevention of tumor hypoxia. Currently it is being tested in phase 2 clinical trials in humans with various tumors. First preclinical evidence also indicates that it can successfully alleviate myocardial hypoxia and prevent adverse left ventricular and right ventricular remodeling in post-myocardial infarction heart failure and pulmonary hypertension. The aim of the article is to summarize the current knowledge on ITTP, as well as to determine the prospects for its potential use in the treatment of many cardiovascular disorders.

Ventricular arrhythmias in acute myocardial ischaemia-Focus on the ageing and sex.

Annually, approximately 17 million people die from cardiovascular diseases worldwide, half of them suddenly. The most common direct cause of sudden cardiac death is ventricular arrhythmia triggered by an acute coronary syndrome (ACS). The study summarizes the knowledge of the mechanisms of arrhythmia onset during ACS in humans and in animal models and factors that may influence the susceptibility to life-threatening arrhythmias during ACS with particular focus on the age and sex. The real impact of age and sex on the arrhythmic susceptibility within the setting of acute ischaemia is masked by the fact that ACSs result from coronary artery disease appearing with age much earlier among men than among women. However, results of researches show that in ageing process changes with potential pro-arrhythmic significance, such as increased fibrosis, cardiomyocyte hypertrophy, decrease number of gap junction channels, disturbances of the intracellular Ca2+ signalling or changes in electrophysiological parameters, occur independently of the development of cardiovascular diseases and are more severe in male individuals. A review of the literature also indicates a marked paucity of research in this area in female and elderly individuals. Greater awareness of sex differences in the aging process could help in the development of personalized prevention methods targeting potential pro-arrhythmic factors in patients of both sexes to reduce mortality during the acute phase of myocardial infarction. This is especially important in an era of aging populations in which women will predominate due to their longer lifespan.

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.

Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate.

Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO2) in PH are lacking. We hypothesized that RV hypoxia occurs in monocrotaline-induced PH in rats and that myo-inositol trispyrophosphate (ITPP), facilitating oxygen dissociation from hemoglobin, can relieve it. Rats received monocrotaline (PH) or saline (control) and 24 days later echocardiograms, pressure-volume loops were obtained and myocardial pO2 was measured using a fluorescent probe. In PH mean pulmonary artery pressure more than doubled (35 ± 5 vs. 15 ± 2 in control), RV was hypertrophied, though its contractility was augmented. RV and LV pO2 was 32 ± 5 and 15 ± 8 mmHg, respectively, in control rats. In PH RV pO2 was reduced to 18 ± 9 mmHg, while LV pO2 was unchanged. RV pO2 correlated with RV diastolic wall stress (negatively) and LV systolic pressure (positively). Acute ITPP administration did not affect RV or LV pO2 in control animals, but increased RV pO2 to 26 ± 5 mmHg without affecting LV pO2 in PH. RV oxygen balance is impaired in PH and as such can be an important target for PH therapy. ITPP may be one of such potential therapies.

Effect of age and sex on the incidence of ventricular arrhythmia in a rat model of acute ischemia.

BACKGROUND: The impact of sex and age on the arrhythmic susceptibility within the setting of acute ischemia is masked by the fact that acute coronary events result from coronary artery disease appearing with age much earlier among men than among women. METHODS AND RESULTS: LAD ligation or sham operations were performed in rats of both sexes at the age 3 and 24 months. An ECG was recorded continuously for 6 h after the operation. The number of early and late premature ventricular beats (PVBs), episodes of ventricular tachycardia (VT) and fibrillation (VF), heart rate, QRS, QT and Tpeak-Tend duration were analysed. Epicardial action potentials were recorded in vivo, Ca2+ signaling was evaluated in isolated cardiomyocytes, fibrosis and connexin-43 expression and localization were measured in the septum. PVBs, VT and VF episodes are much more common in older males than in young males and females independently from their age. Fibrosis with varying intensity in different muscle layers, hypertrophy of cardiomyocytes, reduced number of gap junctions and their appearance on the lateral myocyte membrane, QT prolongation, increase transmural dispersion of repolarisation and a decreased function of SERCA2a may increase the propensity to arrhythmia within the setting of acute ischemia. CONCLUSION: We show that the male sex, especially in case of older individuals is a strong predictor of increased arrhythmic susceptibility within the acute ischemia setting regardless of its impact on the occurrence of cardiovascular diseases. A personalized sex-dependent prevention treatment is needed to reduce the mortality in acute phases of myocardial infarction.

Intravenous ferric carboxymaltose does not provide benefits in reperfused acute myocardial infarction in the rat with normal iron status.

BACKGROUND: Iron deficiency has been implicated in the pathophysiology of heart failure and myocardial ischemia and reperfusion injury. Moreover, reperfused heart seems to lose iron, thus even subjects with normal iron status could benefit from iron therapy. Impaired mitochondrial respiration and energy starvation may be among possible consequences of myocardial iron deficiency. So far no attempts have been made to treat acute coronary syndromes with iron. Thus our aim was to verify the hypothesis that intravenous iron therapy given during reperfusion of an acute myocardial infarction will reduce left ventricular remodeling and hemodynamic abnormalities in a 2-month follow-up as well as early mitochondrial dysfunction and mortality, in the rat with normal iron status. METHODS AND RESULTS: A single dose of ferric carboxymaltose was administered intravenously at 30 min of reperfusion following 30 min of ischemia in the rat model of myocardial infarction. Ventricular arrhythmias were monitored using a telemetric system, activity of mitochondrial enzymes was assessed using spectrophotometry, serum markers of oxidative stress and inflammation were determined and left ventricular function and remodeling were monitored using echocardiography and pressure-volume loops. Intravenous iron therapy did not affect post-myocardial infarction mortality, left ventricular size or function, ventricular arrhythmias, activity of mitochondrial respiratory chain, oxidative stress or markers of inflammation, but was not associated with any adverse effects. CONCLUSIONS: Although ferric carboxymaltose given at reperfusion was safe, it was ineffective in this model of reperfused myocardial infarction in the rat with normal iron status.

Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure.

Chronic heart failure (HF) is often accompanied by systemic iron deficiency (ID). However, effects of ID on cardiac iron status and progression of HF are unknown. To investigate these effects rats underwent LAD ligation to induce post-myocardial infarction HF or sham operation. After 3 weeks the animals from both groups were randomized into three subgroups: control, moderate ID and severe ID+anemia (IDA) by a combination of phlebotomy and low iron diet for 5 weeks. Serum and hepatic iron content were reduced by 55% and 70% (ID) and by 80% and 77% (IDA), respectively, while cardiac iron content was unchanged in HF rats. Changes in expression of all cardiomyocyte iron handling proteins indicating preserved cardiomyocytes iron status in HF and ID/IDA. Contractile function of LV cardiomyocytes, Ca2+ transient amplitude, sarcoplasmic reticulum Ca2+ release and SERCA2a function was augmented by ID and IDA and it was accompanied by an increase in serum catecholamines. Neither ID nor IDA affected left ventricular (LV) systolic or diastolic function or dimensions. To sum up, systemic ID does not result in cardiac ID and does not affect progression of HF and even improves contractile function and Ca2+ handling of isolated LV cardiomyocytes, however, at the cost of increased catecholamine level. This suggests that intravenous iron therapy should be considered as an additional therapeutic option in HF, preventing the increase of catecholaminergic drive with its well-known long-term adverse effects.

Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?

Cardiac arrhythmias are a major source of mortality and morbidity. Unfortunately, their treatment remains suboptimal. Major classes of antiarrhythmic drugs pose a significant risk of proarrhythmia, and their side effects often outweigh their benefits. Therefore, implantable devices remain the only truly effective antiarrhythmic therapy, and new strategies of antiarrhythmic treatment are required. Ivabradine is a selective heart rate-reducing agent, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, currently approved for treatment of coronary artery disease and chronic heart failure. In this review, we focus on the clinical and basic science evidence for the antiarrhythmic and proarrhythmic effects of ivabradine. We attempt to dissect the mechanisms behind the effects of ivabradine and indicate the focus of future studies.

Ivabradine prevents deleterious effects of dopamine therapy in heart failure: No role for HCN4 overexpression.

BACKGROUND: Exacerbations of chronic heart failure (CHF) are often treated with catecholamines to provide short term inotropic support, but this strategy is associated with long-term detrimental hemodynamic effects and increased ventricular arrhythmias (VA), possibly related to increased heart rate (HR). We hypothesized that ivabradine may prevent adverse effects of short-term dopamine treatment in CHF. METHODS: Rats with post-myocardial infarction CHF received 2-week infusion of saline, dopamine(D), ivabradine(I) or D&I; cardiac function was assessed using echocardiography and pressure-volume loops while VA were assessed using telemetric ECG recording. Expression of HCN4, a potentially proarrhythmic channel blocked by ivabradine, was assessed in left ventricular (LV) myocardium. HCN4 expression was also assessed in human explanted normal and failing hearts and correlated with VA. FINDINGS: Dopamine infusion had detrimental effects on hemodynamic parameters and LV remodeling and induced VA in CHF rats, while ivabradine completely prevented these effects. CHF rats demonstrated HCN4 overexpression in LV myocardium, and ivabradine and, unexpectedly, dopamine prevented this. Failing human hearts also exhibited HCN4 overexpression in LV myocardium that was unrelated to patient's sex, CHF etiology, VA severity or plasma NT-proBNP. INTERPRETATION: HR reduction offered by ivabradine may be a feasible strategy to extract benefits of inotropic support in CHF exacerbations, avoiding detrimental effects on CHF biology or VA. Ivabradine may offer additional beneficial effects in this setting, going beyond pure HR reduction, however prevention of ventricular HCN4 overexpression is unlikely to play a major role.

Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat.

Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge. Thus we investigated effects of ivabradine, a presumably specific bradycardic agent versus metoprolol, a ß-blocker, at doses offering the same heart rate (HR) reduction, on ventricular arrhythmias in the acute non-reperfused MI in the rat. Immediately after MI induction a single dose of ivabradine/ metoprolol was given. ECG was continuously recorded and ventricular arrhythmias were analyzed. After 6 h epicardial monophasic action potentials (MAPs) were recorded and cardiomyocyte Ca2+ handling was assessed. Both ivabradine and metoprolol reduced HR by 17% and arrhythmic mortality (14% and 19%, respectively, versus 33% in MI, p < 0.05) and ventricular arrhythmias in post-MI rats. Both drugs reduced QTc prolongation and decreased sensitivity of ryanodine receptors in isolated cardiomyocytes, but otherwise had no effect on Ca2+ handling, velocity of conduction or repolarization. We did not find any effects of potential IKr inhibition by ivabradine in this setting. Thus Ivabradine is an equally effective antiarrhythmic agent as metoprolol in early MI in the rat. It could be potentially tested as an alternative antiarrhythmic agent in acute MI when ß-blockers are contraindicated.

Treatment of hypoxia-dependent cardiovascular diseases by myo-inositol trispyrophosphate (ITPP)-enhancement of oxygen delivery by red blood cells.

Heart failure is a consequence of progression hypoxia-dependent tissue damages. Therapeutic approaches to restore and/or protect the healthy cardiac tissue have largely failed and remain a major challenge of regenerative medicine. The myo-inositol trispyrophosphate (ITPP) is a modifier of haemoglobin which enters the red blood cells and modifies the haemoglobin properties, allowing for easier and better delivery of oxygen by the blood. Here, we show that this treatment approach in an in vivo model of myocardial infarction (MI) results in an efficient protection from heart failure, and we demonstrate the recovery effect on post-MI left ventricular remodelling in the rat model. Cultured cardiomyocytes used to study the molecular mechanism of action of ITPP in vitro displayed the fast stimulation of HIF-1 upon hypoxic conditions. HIF-1 overexpression was prevented by ITPP when incorporated into red blood cells applied in a model of blood-perfused cardiomyocytes coupling the dynamic shear stress effect to the enhanced O2 supply by modification of haemoglobin ability to release O2 in hypoxia. ITPP treatment appears a breakthrough strategy for the efficient and safe treatment of hypoxia- or ischaemia-induced injury of cardiac tissue.

Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities.

Iron is a key micronutrient for the human body and participates in biological processes, such as oxygen transport, storage, and utilization. Iron homeostasis plays a crucial role in the function of the heart and both iron deficiency and iron overload are harmful to the heart, which is partly mediated by increased oxidative stress. Iron enters the cardiomyocyte through the classic pathway, by binding to the transferrin 1 receptor (TfR1), but also through other routes: T-type calcium channel (TTCC), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), Zrt-, Irt-like Proteins (ZIP) 8 and 14. Only one protein, ferroportin (FPN), extrudes iron from cardiomyocytes. Intracellular iron is utilized, stored bound to cytoplasmic ferritin or imported by mitochondria. This cardiomyocyte iron homeostasis is controlled by iron regulatory proteins (IRP). When the cellular iron level is low, expression of IRPs increases and they reduce expression of FPN, inhibiting iron efflux, reduce ferritin expression, inhibiting iron storage and augment expression of TfR1, increasing cellular iron availability. Such cellular iron homeostasis explains why the heart is very susceptible to iron overload: while cardiomyocytes possess redundant iron importing mechanisms, they are equipped with only one iron exporting protein, ferroportin. Furthermore, abnormalities of iron homeostasis have been found in heart failure and coronary artery disease, however, no clear picture is emerging yet in this area. If we better understand iron homeostasis in the cardiomyocyte, we may be able to develop better therapies for a variety of heart diseases to which abnormalities of iron homeostasis may contribute.

A sexy approach to pacemaking: differences in function and molecular make up of the sinoatrial node.

BACKGROUND: Functional properties of the sinoatrial node (SAN) are known to differ between sexes. Women have higher resting and intrinsic heart rates. Sex determines the risk of developing certain arrhythmias such as sick sinus syndrome, which occur more often in women. We believe that a major contributor to these differences is in gender specific ion channel expression. METHODS: qPCR was used to compare ion channel gene expression in the SAN and right atrium (RA) between male and female rats. Histology, immunohistochemistry and signal intensity analysis were used to locate the SAN and determine abundance of ion channels. The effect of nifedipine on extracellular potential recording was used to determine differences in beating rate between sexes. RESULTS: mRNAs for Cav1.3, Kir3.1, and Nkx2-5, as well as expression of the L-Type Ca²âº channel protein, were higher in the female SAN. Females had significantly higher intrinsic heart rates and the effect of nifedipine on isolated SAN preparations was significantly greater in male SAN. Computer modelling using a SAN cell model demonstrated a higher propensity of pacemaker-related arrhythmias in females. CONCLUSION: This study has identified key differences in the expression of Cav1.3, Kir3.1 and Nkx2-5 at mRNA and/or protein levels between male and female SAN. Cav1.3 plays an important role in the pacemaker function of the SAN, therefore the higher intrinsic heart rate of the female SAN could be caused by the higher expression of Cav1.3. The differences identified in this study advance our understanding of sex differences in cardiac electrophysiology and arrhythmias.

Acute Heart Rate-Dependent Hemodynamic Function of the Heart in the Post-Myocardial Infarction Rat Model: Change Over Time.

BACKGROUND: Optimal heart rate (HR) for acute hemodynamic efficiency in heart failure (HF) is unknown. METHODS: Wistar-Kyoto rats were followed-up for 3 and 7 days, 1 or 2 months after myocardial infarction (MI) or sham operation (ShO) and left ventricle (LV) pressure-volume (PV) loops were obtained at various HRs: baseline 400 beats per minute (bpm), reduced by ivabradine to 320 bpm, increased by atrial pacing to 480 bpm, under normal conditions and after preload increase (PI). RESULTS: In the ShO group, PI augmented cardiac output (CO) by 55%, 67%, 84% at reduced, baseline, and increased HR, respectively. In post-MI rats, PI augmented CO 3 and 7 days, but not 1 and 2 months after MI. At increased HR, in response to PI, CO increased 3 and 7 days, tended to fall 1 and 2 months after MI; this hemodynamic response was salvaged by HR reduction. Further beneficial effects of HR reduction included reduction of LV end-diastolic pressure, increase of ejection fraction, contractility and relaxation velocity 1 and 2 months after MI. CONCLUSIONS: In a rat HF model, optimal HR with regard to acute hemodynamic performance is shifted. Whereas in ShO rats increased HR facilitates CO increase induced by PI, in HF rats, such increase reduces CO, and HR reduction has beneficial effects. Thus, besides reducing progression of HF, HR-reducing interventions also offer immediate hemodynamic benefits.

Beneficial effects of intravenous iron therapy in a rat model of heart failure with preserved systemic iron status but depleted intracellular cardiac stores.

Iron deficiency (ID) commonly occurs in chronic heart failure (HF) and is associated with poor prognosis. Neither its causes nor pathophysiological significance are clearly understood. We aimed to assess iron status and the effect of iron supplementation in the rat model of post-myocardial infarction (MI) HF. Four weeks after induction of MI to induce HF or sham surgery, rats received intravenous iron (ferric carboxymaltose) or saline, 4 doses in 1-week intervals. HF alone did not cause anemia, systemic or myocardial ID, but reduced myocardial ferritin, suggesting depleted cardiomyocyte iron stores. Iron therapy increased serum Fe, ferritin and transferrin saturation as well as cardiac and hepatic iron content in HF rats, but did not increase myocardial ferritin. This was accompanied by: (1) better preservation of left ventricular (LV) ejection fraction and smaller LV dilation, (2) preservation of function of Ca2+ handling proteins in LV cardiomyocytes and (3) reduced level of inflammatory marker, CRP. Furthermore, iron supplementation did not potentiate oxidative stress or have toxic effects on cardiomyocyte function, but increased activity of antioxidant defenses (cardiac superoxide dismutase). Despite lack of systemic or myocardial ID we found evidence of depleted cardiomyocyte iron stores in the rat model of HF. Furthermore we observed positive effect of iron supplementation and confirmed safety of iron supplementation in this setting.